2. Academic Validation
  3. Rational Design of Bioorthogonally Activatable PROTAC for Tumor-Targeted Protein Degradation

Rational Design of Bioorthogonally Activatable PROTAC for Tumor-Targeted Protein Degradation

  • J Med Chem. 2023 Oct 23. doi: 10.1021/acs.jmedchem.3c01423.
Tao Bi 1 2,  Pan Liang 1 2,  Yanan Zhou 1 2,  Hong Wang 1 2,  Rui Huang 1 2,  Qin Sun 1 2,  Hongping Shen 1 2,  Sijin Yang 1 2,  Wei Ren 1 2,  Zengjin Liu 1 2
Affiliations

Affiliations

  • 1 National Traditional Chinese Medicine Clinical Research Base and Drug Research Center of the Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University, Chunhui Road, Luzhou 646000, China.
  • 2 Institute of Integrated Chinese and Western Medicine Southwest Medical University, Chunhui Road, Luzhou 646000, China.
PMID: 37871321 DOI: 10.1021/acs.jmedchem.3c01423
Abstract

Protein degradation mediated by the proteolysis-targeting chimera (PROTAC) has emerged as an efficient strategy to accurately control intracellular protein levels. However, the development of PROTACs is limited by their systemic toxicity. Herein, we report a bioorthogonally activatable prodrug (BT-PROTAC) strategy to accurately control the activity of PROTACs. As a proof of concept, we introduced the highly reactive trans-cyclooctene into PROTAC molecule MZ1, the structure-acitivity relationships of which were well characterized previously, to construct the bioorthogonally activatable prodrug BT-PROTAC. Compared with MZ1, BT-PROTAC is incapable of degradation of BRD4 protein. However, BT-PROTAC can be activated by highly active tetrazine compound BODIPY-TZ in vitro. Furthermore, we could selectively degrade BRD4 protein in tumor tissue enabled by tumor-targeted tetrazine compound IR808-TZ. This strategy may represent an alternative to existing strategies and may be widely applied in the design of BT-PROTAC targeting other proteins.

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